Dextroamphetamine is a psychostimulant which is known to produce increased wakefulness and focus in association with decreased fatigue and appetite. It is perhaps the archetypal psycho-stimulant, and drugs with similar psychoactive properties are often referred to as "amphetamine analogues", or described as having "amphetamine-like", or even "amphetaminergic" effects. As a CNS stimulant, enantiopure dextroamphetamine is more powerful than racemicamphetamine and has stimulant properties that are similar to those of methamphetamine, but is slightly less potent.

Dextroamphetamine is the dextrorotarystereoisomer of the amphetamine molecule, which can take two different forms. Other common names for dextroamphetamine include d-amphetamine, dexamphetamine, (S)-(+)-amphetamine, and brand names such as Dexedrine and Dextrostat. It is combined with racemic-amphetamine in the ADHD drug Adderall. It is the active metabolite of the recently introduced prodrug lisdexamfetamine, known by its brand name Vyvanse. In addition, it is an active metabolite of several older N-substituted amphetamine prodrugs used as anorectics, such as clobenzorex (Asenlix), benzphetamine (Didrex) and amphetaminil (Aponeuron).

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Amphetamine was first synthesized under the chemical name "phenylisopropylamine" in Berlin, 1887 by the Romanian chemist Lazar Edeleanu. It was not widely marketed until 1932, when the pharmaceutical company Smith, Kline, and French (currently known as GlaxoSmithKline) introduced it in the form of the Benzedrine Inhaler, for combating cold symptoms. Notably, the chemical form of Benzedrine in the inhaler was the liquid free-base, not a chloride or sulfate salt. In free-base form, amphetamine is a volatile oil, hence the efficacy of the inhalers.

Three years later, in 1935, the medical community became aware of the stimulant properties of amphetamine, specifically dextroamphetamine, and in 1937 Smith, Kline, and French introduced tablets, under the tradename Dexedrine. In the United States, Dexedrine tablets were approved to treat narcolepsy, attention disorders, depression, and obesity. Dextroamphetamine was marketed in various other forms in the following decades, primarily by Smith, Kline, and French, such as several combination medications including a mixture of dextroamphetamine and amobarbital (a barbiturate) sold under the tradename Dexamyl and, in the 1950s, an extended release capsule (the "Spansule").

It quickly became apparent that Dexedrine and other amphetamines had a high potential for abuse, although they were not heavily controlled until 1970, when the Comprehensive Drug Abuse Prevention and Control Act was passed by the United States Congress. Dexedrine, along with other sympathomimetics, was eventually classified as schedule II, the most restrictive category possible for a drug with recognized medical uses.

Internationally, it has been available under the names AmfeDyn (Italy), Curban (US), Obetrol (Switzerland), Simpamina (Italy), Dexedrine (US), and Stild (Spain). [1]

The drug should be avoided for those who have: hypersensitivity to amphetamines, a history of drug abuse, cardiovascular diseases, hypertensive disease, hyperthyroidism, or in those with glaucoma or anorexia nervosa due to the loss of appetite..

Dextroamphetamine use, either for recreational or medical use can induce many different effects as shown below. In general negative effects are increased with increasing dosage amounts, and at medical dosages rarely causes serious adverse effects.

The fatal dose in humans is not precisely known, but in various species of rat generally ranges between 50 and 100 mg/kg, or a factor of 100 over what is required to produce noticeable psychological effects.[14][15]
This suggests a wide therapeutic range[How to reference and link to summary or text], in contrast to such drugs as morphine and heroin, where effective doses may be as much as 50% of a fatal dose[How to reference and link to summary or text]. Although the symptoms seen in a fatal overdose are similar to those of methamphetamine, their mechanisms are not identical, as some substances which inhibit d-amphetamine toxicity do not do so for methamphetamine.[16][17]
Methamphetamine is often considered to be significantly more neurotoxic than d-amphetamine in cases of overdose, particularly to serotonergic and dopaminergic neurons in the CNS.[How to reference and link to summary or text]

An extreme symptom of overdose is amphetamine psychosis, characterized by vivid visual, auditory, and sometimes tactile hallucinations. Many of its symptoms are identical to the psychosis-like state which follows long-term sleep deprivation, so it remains unclear whether these are solely the effect of the drug, or due to the long periods of sleep deprivation which are often undergone by the chronic user or abuser. "In extraordinarily sensitive individuals--such as those with a pre-existing neuropsychiatric disorder--psychosis may be produced by 55 to 75 mg of dextroamphetamine. With high enough doses, psychosis can probably be induced in anyone." Amphetamine psychosis, however, is extremely rare in individuals taking oral amphetamines at therapeutic doses; it is usually seen in cases of prolonged or high-dose intravenous (IV) abuse.[18]

A tablet preparation of the salt d-amphetamine sulfate (pharmaceutical names: Dexedrine or Dextrostat) is available in 5mg and 10mg strengths in the United States. A pharmaceutical with a strength of 10 mg d-amphetamine sulfate is 7.28 mg d-amphetamine base.

Sustained-Release 15 mg Dexedrine Spansules

D-amphetamine sulfate is also available in a controlled release version (pharmaceutical name: Dexedrine SR or Dexedrine Spansule), capsulated in the strengths: 5 mg, 10 mg, and 15 mg.

Dextro-amphetamine is also the active metabolite of the prodruglisdexamfetamine (L-lysine-d-amphetamine) dimesylate (pharmaceutical trade name: Vyvanse). Vyvanse is meant to provide once-a-day dosing because it regulates a slow release of d-amphetamine into the brain. Vyvanse is available as capsules, in six strengths: 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg. The conversion rate of L-lysine-d-amphetamine dimesylate to d-amphetamine base is 0.2948, so a 30 mg-strength Vyvanse capsule is molecularly equivalent to 8.844 mg d-amphetamine base. However, this molecular equivalence would only hold true as a bioequivalence ratio if: the dimesylate salt instantly dissolved resulting in the complete dissociation of L-lysine-d-amphetamine ions, and then the covalent amide bond of every L-lysine-d-amphetamine molecule immediately underwent hydrolysis. In fact, being a prodrug, L-lysine-d-amphetamine has different properties than d-amphetamine; for instance, L-lysine-d-amphetamine is metabolised in the gastrointestinal tract, while d-amphetamine's metabolism is hepatic.[19]

Vyvanse is also being marketed for its lower abuse and misuse potential than when compared to similar drugs such as Adderall, Dexedrine, and the methylphenidate preparations, though it is still rated as a Schedule II drug by the U.S. Drug Enforcement Administration. Vyvanse significantly slower onset and its route of administration is limited to being taken orally, unlike many similar drugs which are commonly nasally insufflated to achieve a much faster onset and higher bioavailability. Since Vyvanse is a prodrug and thus not psychoactive it must be metabolized into d-amphetamine first before having psychoactive effects. Insufflation of Vyvanse is expected to produce no stimulant property, though this is disputed by the DEA.

Aspartate, saccharate, and sulfate salts differ pharmacokinetically in the rate at which they are metabolized by the body. For this and other reasons, Adderall's effects are different from pharmaceuticals with dextroamphetamine as an exclusive active ingredient. Adderall is roughly three-quarters dextroamphetamine, with it accounting for 72.7% of the amphetamine base in Adderall (the remaining percentage is levoamphetamine). Adderall’s inclusion of levoamphetamine provides the pharmaceutical with a quicker onset and longer clinical effect compared to pharmaceuticals exclusively formulated of dextroamphetamine.[20]
Although it seems that where the human brain has a preference for dextroamphetamine over levoamphetamine, it has been reported that certain children have a better clinical response to levoamphetamine.[21]

Though such use remains out of the mainstream, dextroamphetamine has been successfully applied in the treatment of certain categories of depression as well as other psychiatric syndromes.[22]
Such alternate uses include reduction of fatigue in cancer patients, antidepressant treatment for HIV patients with depression and debilitating fatigue,[23] and early stage physiotherapy for severe stroke victims.[24]
If physical therapy patients take dextroamphetamine while they practice their movements for rehabilitation, they learn to move much faster than without dextroamphetamine, and in practice sessions with shorter lengths.[25]

The U.S. Air Force uses dextroamphetamine as one of its two "go pills," given to pilots on long missions to help them remain focused and alert. (Conversely, the Air Force also issues "no-go pills"; prescription sedatives used after the mission to calm down.) [26][27][28][1] The Tarnak Farm incident was linked by media reports to the use of this drug on long term fatigued pilots. A military tribunal did not accept this explanation, citing the lack of similar incidents. Newer stimulant medications with fewer side effects, like modafinil are being investigated and sometimes issued for this reason.[26]

Along with Ritalin and Adderall, illicit use of dextroamphetamine has been reported among students, both as a study aid, social aid, and for purely recreational purposes. According to the National Institute on Drug Abuse, a large percentage of American college students reported non-prescription stimulant use in 2004.[29]

Dextroamphetamine affects dopamine levels in a number of anatomical subsystems in brain, such as the caudate nucleus, the hippocampus and the prefrontal cortex. Because dextroamphetamine is a substrate analog at monoamine transporters, at all doses, dextroamphetamine prevents the reuptake of these neurotransmitters by competing with endogenous monoamines for uptake.[30] Transporter inhibition causes monoamines to remain in the synaptic cleft for a prolonged period (amphetamine inhibits monoamine reuptake in rats with a norepinephrine to dopamine ratio (NE:DA) of about 1:1 and a norepinephrine to 5-hydroxytryptamine ratio (NE:5-HT) of about 1:25).[31] At higher doses, when the concentration of dextroamphetamine is sufficient,[30] the drug can trigger direct release of norepinephrine and dopamine from the cytoplasmic transmitter pool.[32] That is, dextroamphetamine will cause norepinephrine and dopamine efflux via transporter proteins--functionally reversing transporter action, such that the transporters "pump out" catecholamines rather than taking them back up. This inversion leads to a release of large amounts of these transmitters from the cytoplasm of the presynaptic neuron into the synapse, causing increased stimulation of post-synaptic receptors. Dextroamphetamine releases monoamines in rats with selectivity ratios of about NE:DA = 1:3.5 and NE:5-HT = 1:250, meaning that NE and DA are readily released, but release of 5-HT does not occur unless the dose is extraordinarily high.

Dextroamphetamine does not alter glutamate levels in the prefrontal cortex. This may be because dextroamphetamine increases dopamine release in the prefrontal cortex; activation of the dopamine-2 receptors inhibits glutamate release in the prefrontal cortex. However, activation of the dopamine-1 receptors in the prefrontal cortex, increases glutamate leves in the nucleus accumbens. An increase of the glutamate levels in the nucleus accumbens may be part of the reason that dextroamphetamine has an ability to increase locomotor activity in rats. Serotonin may also play a role in dextroamphetamine's affect on glutamate levels; however, at therapeutic doses, dextroamphetamine would likely have little (if any) effect on the serotonin transporter (SERT).[33]

On average, about one half of a given dose is eliminated unchanged in the urine, while the other half is broken down into various metabolites (mostly benzoic acid).[34]
However, the drug's half-life is highly variable because the rate of excretion is very sensitive to urinary pH. Under alkaline conditions, direct excretion is negligible and 95%+ of the dose is metabolized. Having an alkaline stomach will cause the drug to be absorbed faster through the stomach resulting in a higher blood level concentration of amphetamine. Having an alkaline bladder causes the drug to be excreted very slowly. It is possible with acute doses of sodium bicarbonate dissolved in water during amphetamine's course in the body for the half-life of the drug to last about 24 hours, with after effects lasting another 10 hours. The main metabolic pathway is d-amphetamine phenylacetonebenzoic acidhippuric acid. Another pathway, mediated by enzyme CYP2D6, is d-amphetamine p-hydroxyamphetamine p-hydroxynorephedrine. Although p-hydroxyamphetamine is a minor metabolite (~5% of the dose), it may have significant physiological effects as a norepinephrine analogue.[35]

Subjective effects are increased by larger doses, however, over the course of a given dose there is a noticeable divergence between such effects and drug concentration in the blood.[36] In particular, mental effects peak before maximal blood levels are reached, and decline as blood levels remain stable or even continue to increase.[37][38][39]
This indicates a mechanism for development of acute tolerance, perhaps distinct from that seen in chronic use. Its slower onset of action as compared to methamphetamine and methylphenidate is presumably due to a somewhat lower effectiveness in crossing the blood-brain barrier.[40]